The present application is a request for continued funding of a project entitled "Cocaine Discrimination in Humans: Pharmacological Specificity" (DA010325). Recent data indicate that nearly 2 million Americans used cocaine in the past month. Alarmingly, between 1991 and 2001 the number of 8th, 10th, and 12th graders that reported using cocaine in the past 30 days increased 140, 86, and 50 percent, respectively. Thus, cocaine abuse continues to represent a significant public health concern, and will likely remain a problem for the foreseeable future. Intensive research efforts have been aimed at elucidating the neuropharmacological mechanisms that mediate the effects of cocaine. Drug-discrimination studies with laboratory animals that used the substitution and pretreatment methodologies have implicated a prominent role of dopamine in mediating the effects of cocaine. During the initial funding period of this project we used a drug discrimination task and the substitution methodology to demonstrate that dopamine systems are involved in mediating the discriminative-stimulus effects of cocaine in humans. We are not aware of any published studies in which the discriminative-stimulus effects of cocaine were assessed in humans following pretreatment with another drug even though drug-discrimination procedures may be particularly well suited for studying agonist-antagonist interactions. The aim of this application is to further characterize the role of dopamine in mediating the discriminative-stimulus effects of cocaine in humans using a pretreatment methodology. To accomplish this aim, 3 laboratory experiments will be conducted with volunteers with histories of cocaine abuse. The discriminative-stimulus and subjective effects of cocaine will be assessed alone and following pretreatment with mazindol, a dopamine uptake blocker (Exp. 1); fluphenazine, a D1-D2 dopamine receptor antagonist (Exp. 2); and haloperidol, a D2 dopamine receptor antagonist (Exp. 3). We predict that pretreating volunteers with a dopamine agonist or antagonist will shift the cocaine dose-response curve, leftward and rightward, respectively. The experiments proposed in this "proof-of-concept" continuation application will provide additional information concerning the role of dopamine in mediating the discriminative-stimulus effects of cocaine in humans. Elucidating the role of dopamine in mediating the effects of cocaine may guide the development of pharmacological interventions for cocaine.